ABSTRACT Delirium, an acute state of inattention and confusion often precipitated by hospitalization and surgery, is a condition for which patients with neurodegenerative diseases such as dementia due to Alzheimer's disease (AD) are especially vulnerable. Evidence is mounting that people who do not have dementia at the time they experience delirium are at increased risk for long-term cognitive decline (LTCD) and future dementia; whether underlying AD pathology consistent with preclinical AD accounts for this heightened risk of delirium and adverse outcomes is not known. In the prior cycle of this Project, a number of findings from diffusion tensor imaging and fluid biomarkers associated with inflammation were identified as predisposing to delirium. However, it is not clear whether those biomarkers might have been associated with preclinical AD pathology, vulnerable aging, or other known pathologies. Using modern magnetic resonance imaging (MRI) techniques, we have identified an ?AD-Signature? of cortical atrophy and hippocampal hyperactivation as biomarkers of prodromal or preclinical AD. In addition, measures of changes in the brain that are associated with age-related cognitive decline in the absence of neurodegenerative or cerebrovascular disease can be detected as a ?Vulnerable Aging-Signature? of cortical atrophy and reduced frontoparietal functional connectivity. Therefore, the overarching goal of this proposal is to examine whether neuroimaging biomarkers of preclinical AD or vulnerable aging are predictive of delirium, delirium severity, and complicated delirium (i.e., delirium with LTCD), and to link these neuroimaging biomarkers to molecular biomarkers of pathology measured in the cerebrospinal fluid (CSF) and plasma. The Specific Aims are: 1) to determine in people with evidence of preclinical AD (i.e. patients with abnormal CSF AD biomarker levels of tau and beta-amyloid) whether AD- related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; 2) to determine in people without evidence of preclinical AD (i.e. patients with normal CSF AD biomarkers) whether vulnerable aging-related brain atrophy or network dysfunction are associated with delirium, delirium severity, or LTCD; and 3) to investigate whether longitudinal cortical atrophy (measured pre-operatively and one year after surgery) due to preclinical AD or vulnerable aging is associated with postoperative LTCD or complicated delirium. To test these hypotheses, we will leverage the resources of P01AG031720 which generated the original SAGES I cohort (N=560 total, n=126 with longitudinal MRI), augmented by new CSF and MRI data collected in 128 SAGES I probability sampled patients (64 with delirium, 64 without) about four years after their surgery, and a new SAGES II cohort (N=400), of which 180 patients will have both CSF and MRI collected pre- operatively. The long-term objective of this Project is to improve the pathophysiological understanding of brain vulnerability to delirium in order to inform prevention strategies and, ultimately, pathophysiological-based treatments.